This project will continue to characterize in dogs the role of hepatic extraction of insulin, glucagon, somatostatin and pancreatic ploypeptide in the regulation of peripheral concentrations of these substances under different physiological conditions. While approximately 50% of the insulin presented to the liver is removed in a single transhepatic passage, much less glucagon is extracted. These studies uuilized anesthetized dogs with catheters in the femoral artery, portal vein and left common hepatic vein and electromagnetic flow probes on the portal vein and hepatic artery. When increased amounts of insulin and glucagon were presented to the liver either as a consequence of arginine, cholecystokinin-pancreozymine infusion or administration of exogenous insulin and glucagon, hepatic extraction of insulin significantly decreased without a concomitant alteration in hepatic extraction of glucagon. Upon cessation of these infusions the amounts of the hormones presented to the liver returned to normal and the hepatic extraction of insulin increased to control values. In contrast, hepatic extraction of glucagon continued to decrease and sometimes more glucagon left the liver than was presented to it. Portal vein insulin/glucagon ratios correlated quite well with change in hepatic glucose production but this was not true for peripheral vessel insulin/ glucagon ratios. These data demonstrate that peripheral vein insulin/glucagon ratios cannot be utilized to predict alterations in hepatic glucose production. These studies will now be extended to investigate hepatic extraction of pancreatic polypeptide and somatostatin and the effects of substances which increase their secretion as well as that of insulin and glucagon will be examined. The influence of the heterogeneity of plasma glucagon on the observed hepatic extraction of this hormone will be investigated. We shall examine the effects of administration of various hormones for several days prior to the measurement of hepatic extraction of insulin, glucagon, pancreatic polypeptide and somatostatin.